Gene Expression Patterns in Hepatic Tissue and Visceral Adipose Tissue of Patients with Non-Alcoholic Fatty Liver Disease

Baranova, Ancha; Schlauch, Karen; Elariny, Hazem; Jarrar, Mohammed; Bennett, C.; Nugent, Clare; Gowder, S.; Younoszai, Zahra; Collantes, Rochelle; Chandhoke, Vikas; Younossi, Zobair M.

doi:10.1007/s11695-007-9187-y

Cited by 51 publications

(42 citation statements)

References 28 publications

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“…Previous studies have examined gene expression changes in human NAFLD livers classified as steatotic (Greco et al, 2008) and in livers classified as NASH using various microarray platforms (Younossi et al, 2005a;Baranova et al, 2007;Rubio et al, 2007). These studies confirm that liver disease status alters gene expression changes.…”

Section: Discussionsupporting

confidence: 55%

Analysis of Global and Absorption, Distribution, Metabolism, and Elimination Gene Expression in the Progressive Stages of Human Nonalcoholic Fatty Liver Disease

Lake¹,

et al. 2011

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ABSTRACT:Nonalcoholic fatty liver disease (NAFLD) is characterized by a series of pathological changes that range from simple fatty liver to nonalcoholic steatohepatitis (NASH). The objective of this study is to describe changes in global gene expression associated with the progression of human NAFLD. This study is focused on the expression levels of genes responsible for the absorption, distribution, metabolism, and elimination (ADME) of drugs. Differential gene expression between three clinically defined pathological groups-normal, steatosis, and NASH-was analyzed. Genome-wide mRNA levels in samples of human liver tissue were assayed with Affymetrix GeneChip Human 1.0ST arrays. A total of 11,633 genes exhibited altered expression out of 33,252 genes at a 5% false discovery rate. Most gene expression changes occurred in the progression from steatosis to NASH. Principal component analysis revealed that hepatic disease status was the major determinant of differential ADME gene expression rather than age or sex of sample donors. Among the 515 drug transporters and 258 drug-metabolizing enzymes (DMEs) examined, uptake transporters but not efflux transporters or DMEs were significantly over-represented in the number of genes downregulated. These results suggest that uptake transporter genes are coordinately targeted for down-regulation at the global level during the pathological development of NASH and that these patients may have decreased drug uptake capacity. This coordinated regulation of uptake transporter genes is indicative of a hepatoprotective mechanism acting to prevent accumulation of toxic intermediates in disease-compromised hepatocytes.

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Section: Discussionsupporting

confidence: 55%

Analysis of Global and Absorption, Distribution, Metabolism, and Elimination Gene Expression in the Progressive Stages of Human Nonalcoholic Fatty Liver Disease

Lake¹,

et al. 2011

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“…[10][11][12] In obese subjects, both pathways are stimulated by the soluble molecules produced by excessive white adipose tissue. Furthermore, many genes differentially expressed in the white adipose tissue of patients with NAFLD are linked to the processes of insulin resistance or inflammation.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, many genes differentially expressed in the white adipose tissue of patients with NAFLD are linked to the processes of insulin resistance or inflammation. 11,12 It is possible that many of these targets are directly or indirectly regulated by miRNAs. Indeed, many molecules previously noted as differentially expressed in patients with NASH, such as V-rel reticuloendotheliosis viral oncogene homolog A (RELA) and STEAP family member 4 (STEAP4 ⁄ STAMP2), 13,14 have previously been identified in the miRanda database as potential targets of multiple miRNAs.…”

Section: Discussionmentioning

confidence: 99%

Differential expression of miRNAs in the visceral adipose tissue of patients with non‐alcoholic fatty liver disease

Estep

Armistead

Hossain

et al. 2010

Aliment Pharmacol Ther

125

115

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Aliment Pharmacol Ther 2010; 32: 487–497SummaryBackground Progression of non‐alcoholic fatty liver disease (NAFLD) can be facilitated by soluble molecules secreted by visceral adipose tissue (VAT). MicroRNAs (miRNAs) are likely to regulate some of these molecular pathways involved in pathogenesis of NAFLD.Aim To profile miRNA expression in the visceral adipose tissue of patients with NAFLD.Methods Visceral adipose tissue samples were collected from NAFLD patients and frozen. Patients with biopsy‐proven NAFLD were divided into non‐alcoholic steatohepatitis (NASH) (n = 12) and non‐NASH (n = 12) cohorts controlled for clinical and demographic characteristics. Extracted total RNA was profiled using TaqMan Human MicroRNA arrays. Univariate Mann–Whitney comparisons and multivariate regression analysis were performed to compare miRNA profiles.Results A total of 113 miRNA differentially expressed between NASH patients and non‐NASH patients (P < 0.05). Of these, seven remained significant after multiple test correction (hsa‐miR‐132, hsa‐miR‐150, hsa‐miR‐433, hsa‐miR‐28‐3p, hsa‐miR‐511, hsa‐miR‐517a, hsa‐miR‐671). Predicted target genes for these miRNAs include insulin receptor pathway components (IGF1, IGFR13), cytokines (CCL3, IL6), ghrelin/obestatin gene, and inflammation‐related genes (NFKB1, RELB, FAS). In addition, two miRNA species, hsa‐miR‐197 and hsa‐miR‐99, were significantly associated with pericellular fibrosis in NASH patients (P < 0.05). Levels of IL‐6 in the serum negatively correlated with the expression levels of all seven miRNAs capable of down regulating IL‐6 encoding gene.Conclusions miRNA expression from VAT may contribute to the pathogenesis of NAFLD – a finding which may distinguish relatively simple steatosis from NASH. This could help identify potential targets for pharmacological treatment regimens and candidate biomarkers for NASH.

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“…[7][8][9] In fact, in recent years, significant information in the understanding of NAFLD pathogenesis has been gained by examining the data accumulated by high-throughput technologies. 10,11 Often a single approach is not sufficient to give a comprehensive picture of hepatic dysfunctions occurring in NAFLD, and somewhat, a multiple-approach combination of different techniques is recommended. 12 Calvert et al 13 showed a good example of integration of system biology with reverse-phase protein microarray analysis to define genetic architecture of NAFLD.…”

mentioning

confidence: 99%

Mirnome analysis reveals novel molecular determinants in the pathogenesis of diet-induced nonalcoholic fatty liver disease

Alisi

Sacco

Bruscalupi

et al. 2011

Laboratory Investigation

178

116

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Nonalcoholic fatty liver disease (NAFLD) is an emerging disease with a broad spectrum of liver conditions. The complex molecular pathogenesis of NAFLD is still unclear. In this study, we conducted an analysis of microRNA (miRNA) expression profiles in liver of rats made NAFLD by different diets. To this aim, Sprague-Dawley rats were fed ad libitum for 3 months with different diets: standard diet (SD), diet enriched in fats and low in carbohydrates (HFD), SD with high fructose (SD-HF) and diet with high levels of fats and fructose (HFD-HF). Our results demonstrated that the treatment with different dietetic regimens caused a significant increase of the body weight and the alteration of some metabolic parameters compared with control animals, as well as various liver injuries. The miRNAs analysis showed the significant downregulation of three miRNAs (miR-122, miR-451 and miR-27) and the upregulation of miR-200a, miR-200b and miR-429 in HFD, SD-HF and HFD-HF rats. Besides, miR-21 expression was significantly decreased only in fructose-enriched diets. These miRNAs target molecules involved in the control of lipid and carbohydrate metabolism, signal transduction, cytokine and chemokine-mediated signaling pathway and apoptosis. Western blot analysis of PKCd, LITAF, ALDOLASE-A, p38MAPK, PTEN, LIPIN1, EPHRIN-A1, EPHA2 and FLT1 showed a diet-induced deregulation of all these proteins. Interestingly, the expression pattern of LITAF, PTEN, LIPIN1, EPHRIN-A1, EPHA2 and FLT1 might be well explained by the trend of their specific mRNAs, by potentially regulatory miRNAs, or both. In conclusion, we highlight for the first time the potential involvement of novel determinants (miRNAs and proteins) in the molecular pathogenesis of diet-induced NAFLD.

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Gene Expression Patterns in Hepatic Tissue and Visceral Adipose Tissue of Patients with Non-Alcoholic Fatty Liver Disease

Abstract: Our findings support the hypothesis that adipocyte secretion plays an important role in the development of NAFLD.

Cited by 51 publications

References 28 publications

Analysis of Global and Absorption, Distribution, Metabolism, and Elimination Gene Expression in the Progressive Stages of Human Nonalcoholic Fatty Liver Disease

Analysis of Global and Absorption, Distribution, Metabolism, and Elimination Gene Expression in the Progressive Stages of Human Nonalcoholic Fatty Liver Disease

Differential expression of miRNAs in the visceral adipose tissue of patients with non‐alcoholic fatty liver disease

Mirnome analysis reveals novel molecular determinants in the pathogenesis of diet-induced nonalcoholic fatty liver disease

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